Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data
Introduction
Tocilizumab (TCZ) is a recombinant humanized anti-interleukin-6-receptor monoclonal IgG antibody that inhibits the IL-6-mediated signaling pathway [1]. Clinical trials of TCZ demonstrate the therapeutic effectiveness of IL-6 receptor signaling inhibition in patients with rheumatoid arthritis (RA) with inadequate response to disease-modifying antirheumatic drugs (DMARDs), or tumor necrosis factor (TNF) α antagonists [2]. Currently, TCZ has received approval in more than 75 countries worldwide for RA and more recently also for systemic juvenile idiopathic arthritis in children [3]. Efficacy and safety of TCZ as monotherapy or in combination with DMARDs in RA patients insufficiently responsive to DMARDs, or TNF-α-antagonist therapy have been shown [4], [5].
Preclinical data from experimental animal studies suggest that blockade of IL-6-receptor signaling induces no apparent biological effects on fertility or prenatal/postnatal development [6]. TCZ administered to cynomolgus monkeys during early gestation was observed to have no direct or indirect harmful effect on pregnancy or embryo–fetal development. However, a slight increase in abortion/fetal death was observed with high systemic exposure (>100× human exposure) in the 50 mg/kg/day high-dose group compared to placebo and lower doses [7]. Human experience with TCZ exposure in pregnancy is limited to abstracts from conferences [8].
Use of TCZ is not recommended during pregnancy because information regarding the safety of TCZ during pregnancy is extremely limited. However, as many pregnancies are unplanned and RA often concerns women of childbearing potential, there is a need for data to counsel pregnant women inadvertently exposed to TCZ. The evaluation of pregnancy cases from the Roche Global Safety Database is expected to provide basic information in managing pregnancies with TCZ treatment.
Section snippets
Materials and methods
The Roche Global Safety Database records information on pregnancy cases received from clinical trials, spontaneous reports, non-interventional programs or non-interventional studies, and published literature for all Roche products. The pregnancy and neonatal topics MedDRA Standard Query (SMQ) v17.1 was used to retrieve TCZ pregnancy cases from the Roche Global Safety Database, cumulatively up to December 31, 2014.
Pregnancy reports were evaluated independently by two authors (E. Beck and M.
Results
A total of 501 pregnancy-related reports were retrieved from the Roche Global Safety Database until December 31, 2014 (Fig. 1). Most reports concerned maternal exposure and only 22 were related to exposure of the future father. After exclusion of ongoing pregnancies, duplicates, and cases retrieved from the literature, 399 women were exposed to TCZ before or during pregnancy; pregnancy outcome was reported in 288 (72.2%) of these pregnancies. Prospectively and retrospectively reported patients
Discussion
Our pregnancy outcome study includes the largest dataset of patients with preconception or first trimester exposure to TCZ.
Neither among our 180 prospectively reported pregnancies nor among the 108 retrospective cases a substantially increased rate of congenital malformations was reported, nor was there a distinct pattern of malformations. In most patients of the preconception group (46/54 = 85%) exposure with TCZ occurred during the 6 weeks before conception. Assuming a half-life of 8–14 days
Disclosure statement
Maria Hoeltzenbein, Evelin Beck, Carina Skorpen, and Christof Schaefer declare no conflict of interest. Richa Rajwanshi and Erhan Berber are employees of Genentech/Roche. Monika Ostensen has received speakers fees (<10.000$) from Abbott/Abbvie, Mepha, New Bridge, Pfizer, Roche, and UCB.
Monika Ostensen, Maria Hoeltzenbein, Evelin Beck, Carina Skorpen, Christof Schaefer, Erhan Berber, and Richa Rajwanshi designed the study and revised the manuscript, Erhan Berber and Richa Rajwanshi provided the
Acknowledgements
This work was performed with financial support from the German Ministry of Health (BMG) and the German Federal Institute for Drugs and Medical Devices (BfArM).
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